Cornelia de Lange Syndrome is a complex congenital malformations syndrome with many post-natal progressive medical complications. CdLS has a clear genetic cause with loss of function mutations in NIPBL accounting for over 65% of the genetically confirmed CdLS cases. The remaining cases exhibit mutations in subunits or regulators of the cohesion complex (SMC3, SMCA1, HDAC8, and RAD21). The pathophysiology of the disease is unclear and the set of symptoms are variable and complex. These many complications have prevented the identification of new treatments. Recursion Pharmaceuticals has developed a high-throughput method for modeling monogenic loss of function diseases, such as CdLS, in human cellular models. This grant expects to find a repurposed drug for treatment of CdLS by: 1. Developing siRNA induced loss of function models of CdLS mutations including NIPBL, HDAC8, and RAD21 in multiple human cell types. 2. Creating a disease phenoprint by compiling hundreds of significantly changed structural (morphological) parameters after loss of NIPBL, HDAC8, or RAD21. 3. Screen loss of function cellular lines using drug discovery platform to reveal known drugs that significantly reverse the structural disease phenotype. 4. Confirm the drug is using its known mechanism of action in CdLS rescued cellular lines Recursion has proven this platform successful with the identification of two known drugs for repurposing in another rare loss of function disease, cerebral cavernous malformation (CCM).